Ischemic heart diseases including myocardial infarction, arrhythmia and angina pectoris, caused by the myocardial injury and dysfunction that are attributed to ischemia/reperfusion, show high mortality and prevalence rate, and can not be perfectly cured. Thus, intensive scientific and clinical studies on its treatment have been made for the past five decades [Wang, Q D. et al., (2002) Cardiovasc. Res. 55: 25-37].
Ischemia/reperfusion injury is related to various physiological mechanisms such as metabolic changes, immune responses, perturbation of ionic homeostasis, oxygen free radicals, etc. Thus, in order to understand ischemia/reperfusion injury, studies on immune regulators, apoptosis related substances and ion channel regulators, are all relevant [Hearse, D J.(1998) Prog. Cariovasc. Dis. 30: 381-402]. In addition to the studies on mechanisms, new therapeutic approaches and surgical procedures have been actively investigated. However, any novel technique to protect myocardial cells from ischemia/reperfusion has not been adopted clinically, yet. Even after the reperfusion therapy including surgical operations such as coronary artery bypass graft (CABG) and percutaneous transluminal coronary angioplasty (PTCA), and the use of thrombolytics, reperfusion injury such as myocardial infarction, arrhythmia, angina pectoris, decrease of neurocognitive ability, etc, is frequently reported [Robert, M. (2003) Ann. Thorac. Surg. 75: S700-708]. Therefore, it is an urgent need to develop a safe and effective therapy to slow down the progression of myocardial ischemic injury and attenuate the injury by reperfusion.
NHEs (sodium-hydrogen exchangers) are ion transporters expressed in a variety of cells that maintains intracellular pH homeostasis by the electroneutral exchange of intracellular H+ for extracellular Na+. 7 isoforms of NHE have been identified so far, and among them, NHE-1, the major subtype in myocardial cells, has been known to be deeply involved in ischemia/reperfusion injury [Avkiran, M. et. al., (2002) J. Am. Coll. Cardiol. 39: 747-753]. NHE-1 is generally inacive under normal physiological pH (≈7.2). Ischemia brings a rapid fall of intracellular pH (pH≈6.4), more precisely, the production of energy depends on glycolysis under ischemic condition because of the lack of oxygen, resulting in the increase of H+ content in the cell. Then, NHE-1 which has a proton sensor is activated to extrude H+ and to move Na+ into the cell resulting in the increase of intracellular Na+. Ischemia induced the inhibition Na+/K+ ATPase which is the primary Na+ extrusion pathway from the cardiac myocyte, so that intracellular Na+ is accumulated. Such an increase of intracellular Na+ alters the sarcolemmal Na+/Ca2+ exchanger (NCX) to the reversal mode in a manner that inhibits Ca2+ efflux and/or enhances Ca2+ influx through this bi-directional mechanism, resulting in a pathologic increase in intracellular Ca2+. This intracellular Ca2+ overload is assumed to be involved in ischemic and reperfusion injuries by the decomposition of proteins via the activation of protease, phospholipase and endonuclease, the increase of oxygen free radicals via the defect of fat metabolism, and the mutation of DNA, etc. The inhibition of NHE-1 limits the intracellular Na+ and Ca2+ overload, which affords the presumable mechanism for cardioprotection against ischemia/reperfusion. The inhibition of NHE-1 does not induce intracellular acidosis because the increased intracellular H+ can be regulated through another ion transpoters. Amiloride, a pyrazin derivative, known as a diuretic, is the first known NHE inhibitor [Benos, D J. (1982) A. J. Physiol. 242: C131]. Amiloride has been confirmed, in experiments using isolated rat hearts, to inhibit NHE-1 and to improve the recovery of cadiac function after ischemia/reperfusion, but showed side effects at the same time such as the additional inhibition on NHE-2 and sodium channel. Thus, it can not used as a cardioprotective agent because of poor selectivity. Studies have been made to discover a NHE-1 selective inhibitor, and NHE-1 selective cariporide (HOE-694), a benzoylguanidine derivative, has been developed by Hoechst Marion Roussel (Aventis) [Scholz, W. et. al., (1993) Br. J. Pharmacol. 109: 562]. Cariporide showed excellent cardiac protective effect in animal models and also showed significant protective effect in a patient undergoing CBGA surgery. Most NHE-1 inhibitors, known so far, have acylguanidine moiety as a pharmacophoric unit such as eniporide, zoniporide, SM-20220, BMS-284640, etc.

The NHE-1 inhibitor has been proven to improve myocardial contractility and metabolic status, and to reduce arrhythmia, apoptosis, necrosis, and intracellular overload of Na+ and Ca2+, indicating that it has a cardioprotective effect against ischemia/reperfusion injury [Karmazyn, M. (2002) Science & Medicine: 18-26]. Thus, NHE-1 selective inhibitor can be effectively used for the prevention and the treatment of ischemic heart diseases such as acute myocardial infarction, arrhythmia, angina pectoris, etc, and also a promising candidate for a heart protecting agent applied to reperfusion therapy or cardiac surgery including coronary artery bypass graft, percutaneous transluminal coronary angioplasty, etc.